Antibody Vh Repertoire Differences between Resolving and Chronically Evolving Hepatitis C Virus Infections

Abstract

Despite the production of neutralizing antibodies to hepatitis C virus (HCV), many patients fail to clear the virus and instead develop chronic infection and long-term complications. To understand how HCV infection perturbs the antibody repertoire and to identify molecular features of antibody genes associated with either viral clearance or chronic infection, we sequenced the V(D)J region of naïve and memory B cells of 6 persons who spontaneously resolved an HCV infection (SR), 9 patients with a newly diagnosed chronically evolving infection (CE), and 7 healthy donors. In both naïve and memory B cells, the frequency of use of particular antibody gene subfamilies and segments varied among the three clinical groups, especially between SR and CE. Compared to CE, SR antibody genes used fewer VH, D and JH gene segments in naïve B cells and fewer VH segments in memory B cells. SR and CE groups significantly differed in the frequency of use of 7 gene segments in naïve B cell clones and 3 gene segments in memory clones. The nucleotide mutation rates were similar among groups, but the pattern of replacement and silent mutations in memory B cell clones indicated greater antigen selection in SR than CE. Greater clonal evolution of SR than CE memory B cells was revealed by analysis of phylogenetic trees and CDR3 lengths. Pauciclonality of the peripheral memory B cell population is a distinguishing feature of persons who spontaneously resolved an HCV infection. This finding, previously considered characteristic only of patients with HCV-associated lymphoproliferative disorders, suggests that the B cell clones potentially involved in clearance of the virus may also be those susceptible to abnormal expansion.

HCV Proteins and Immunoglobulin Variable Gene (IgV) Subfamilies in HCV-Induced Type II Mixed Cryoglobulinemia: A Concurrent Pathogenetic Role

“…Moreover, similar characteristics were observed also for anti-protein Abs produced in the context of chronic systemic autoimmune diseases [96]. Conversely, for HCV infection, a recent paper reported a shorter CDR3 length of the Ab repertoire in people who spontaneously resolved an acute HCV infection compared to healthy individuals and those with chronically evolving HCV infection, and the authors explain this difference suggesting a mobilization of the Ab repertoire due to clonal selection [76]. …”

Novel E2 Glycoprotein Tetramer Detects Hepatitis C Virus–Specific Memory B Cells

“…The BCR repertoire of bulk memory and naive B cells was previously investigated during HCV infection (45). However, in this study total memory B cells as opposed to antigen-specific cells were analyzed.…”

Molecular Signatures of Hepatitis C Virus (HCV)-Induced Type II Mixed Cryoglobulinemia (MCII)

“…This finding, considered characteristic only of patients with HCV-associated lymphoproliferative disorders, suggests that the B-cell clones potentially involved in clearance of the virus may also be subjected to abnormal proliferation [122]. However, it is widely accepted that the intrinsic genetic instability of B cells during somatic hypermutation and class-switching processes, may favor genetic aberrations responsible for prolonged B-cell survival and proliferation, thus allowing them to escape from the homeostatic balance controlling clonal expansion.…”